Vasoconstriction by in situ formed angiotensin II: role of ACE and chymase

Objective: To assess the importance, for vasoconstriction, of in situ angiotensin (Ang) II generation, as opposed to Ang LI delivery to AT receptors via the organ bath fluid, Methods: Ang I and II concentration-response curves in human and porcine coronary arteries (HCAs, PCAs) were constructed in relation to estimates of the clearances of Ang I and II (Cl-AngI Cl-AngII) from the organ bath and the release of newly formed Ang II (R-AngII) into the bath fluid. HCAs were from 25 heart valve donors (age 5-54 years), and PCAs from 14 pigs (age 3 months). Results: Ang I- and II-evoked constrictions were inhibited by the AT(1) receptor antagonist, irbesartan, and were not influenced by the AT(2) receptor antagonist, PD123319. In HCAs Ang II was only three times more potent than Ang I, whereas, in the experiments with Ang I, comparison of Cl-AngI with Cl-AngII and R-AngII indicated that most of the arterially produced Ang II did not reach the bath fluid. Also in PCAs Ang I and II showed similar potency. In HCAs both the ACE inhibitor, captopril, and the chymase inhibitor, chymostatin, inhibited Ang I-evoked vasoconstriction, while only chymostatin had a significant effect on Cl-AngI. In PCAs Ang I-evoked vasoconstriction was almost completely ACE-dependent. Conclusions: This study points towards the functional importance of in situ ACE- and chymase-dependent Ang LI generation, as opposed to Ang II delivery via the circulation. It also indicates that functionally relevant changes in local Ang I-II conversion are not necessarily reflected by detectable changes in circulating Ang II. (C) 1999 Elsevier Science BN. All rights reserved.